EP2265582B1 - Neuartige 3-aminoalkyl-1,3-dihydro-2h-indol-2-on-derivate, ihre herstellung und therapeutische verwendung - Google Patents

Neuartige 3-aminoalkyl-1,3-dihydro-2h-indol-2-on-derivate, ihre herstellung und therapeutische verwendung Download PDF

Info

Publication number
EP2265582B1
EP2265582B1 EP09721627A EP09721627A EP2265582B1 EP 2265582 B1 EP2265582 B1 EP 2265582B1 EP 09721627 A EP09721627 A EP 09721627A EP 09721627 A EP09721627 A EP 09721627A EP 2265582 B1 EP2265582 B1 EP 2265582B1
Authority
EP
European Patent Office
Prior art keywords
methoxy
dihydro
indol
sulfonyl
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP09721627A
Other languages
English (en)
French (fr)
Other versions
EP2265582A1 (de
Inventor
Loïc FOULON
Laurent Goullieux
Brigitte Pouzet
Claudine Serradeil-Le Gal
Gérard Valette
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi SA filed Critical Sanofi SA
Publication of EP2265582A1 publication Critical patent/EP2265582A1/de
Application granted granted Critical
Publication of EP2265582B1 publication Critical patent/EP2265582B1/de
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to novel 3-aminoalkyl-1,3-dihydro-2 H- indol-2-one, their preparation and their therapeutic application.
  • the compounds according to the present invention have a high affinity and a high selectivity for human V 1a receptors of arginine-vasopressin (AVP) and certain compounds according to the invention also have a high affinity for V 1b receptors. AVP.
  • AVP is a hormone known for its antidiuretic effect and its effect in the regulation of blood pressure. It stimulates several types of receivers: V 1 (V 1a , V 1b ), V 2 . These receptors are located in particular in the liver, the vessels (coronary, renal, cerebral), platelets, kidney, uterus, adrenal glands, pancreas, central nervous system, pituitary gland. AVP thus exerts cardiovascular, hepatic, pancreatic, antidiuretic, platelet aggregating effects and effects on the central and peripheral nervous system, and on the uterine sphere.
  • V 1a receptors of AVP are localized in many peripheral organs and in the brain. They have been cloned in rats and humans and they regulate the majority of the known effects of AVP: platelet aggregation; uterine contractions; the contraction of the vessels; contraction of renal mesangial cells, secretion of aldosterone, cortisol, corticotropin-releasing factor (CRF) and adrenocorticotrophic hormone (ACTH); hepatic glycogenolysis, cell proliferation and the main central effects of AVP (hypothermia, memory, anxiety, affiliation ).
  • the adrenal cortex is also rich in receptors.
  • V 1a involved in the production of gluco- and mineralo-corticoids (aldosterone and cortisol).
  • AVP circulating or synthesized locally
  • Cortisol is a potent regulator of the production of ACTH, the stress hormone.
  • V 1a receptors are also a more specific marker of small cell lung cancer (SCLC) ( PJ Woll et al., Biochem. Biophys. Res. Commun., 1989, 164 (1), 66-73 ).
  • SCLC small cell lung cancer
  • the compounds according to the present invention are obvious diagnostic tools and offer a new therapeutic approach to control the proliferation of these tumors and their detection, at a very early stage (radiolabeling) SPECT, of the English Single Photon Emission Computed Tomography PET Scan, English Positron Emission Tomography Scanner).
  • V 1b receptors were initially identified in the adenohypophysis of different animal species (rat, pig, beef, sheep ...) including in humans ( S. Jard et al., Mol. Pharmacol., 1986, 30, 171-177 ; Y. Arsenijevic et al., J. Endocrinol., 1994, 141, 383-391 ; J. Schwartz et al., Endocrinology, 1991, 129 (2), 1107-1109 ; Y.
  • V 1b receptors have been cloned in rats, humans and mice ( Y. de Keyser, FEBS Letters, 1994,356, 215-220 ; T. Sugimoto et al., J. Biol. Chem., 1994, 269 (43), 27088-27092 ; M. Saito et al., Biochem. Biophys. Res.
  • AVP via these receptors would have a crucial role in certain types of adrenal pheochromocytoma secreting AVP and thereby inducing sustained production of catecholamines causing hypertension resistant to receptor antagonists.
  • angiotensin II and angiotensin converting enzyme inhibitors The adrenal cortex is also rich in V 1a receptors involved in the production of gluco- and mineralocorticoids (aldosterone and cortisol).
  • AVP circulating or synthesized locally
  • Cortisol is a potent regulator of the production of ACTH, the stress hormone.
  • V 1b receptors are also considered as a marker of secreting ACTH tumors such as certain pituitary tumors, certain bronchial carcinomas (small cell lung cancer or SCLC), pancreatic, adrenal and thyroid cancers, inducing Cushing's syndrome in some cases ( J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173 ; GA Wuinert et al., Lancet, 1990,335, 991-994 ; G. Dickstein et al., J. Clin. Endocrinol. Metab., 1996, 81 (8), 2934-2941 ).
  • V 1a receptors are, in turn, a more specific marker of small cell lung cancer (SCLC) ( PJ Woll et al., Biochem. Biophys. Res. Commun., 1989, 164 (1), 66-73 ).
  • SCLC small cell lung cancer
  • the compounds according to the present invention are obvious diagnostic tools and offer a new therapeutic approach in the proliferation and detection of these tumors, at an early stage (radiolabeling, SPECT, of the English Single Photon Emission Computed Tomography; PET Scan, English Positron Emission Tomography Scanner).
  • V 1b receptors The abundant presence of the messenger of the V 1b receptors at the stomach and intestinal level, suggests an involvement of the AVP via this receptor on the release of gastrointestinal hormones such as cholecystokinin, gastrin or secretin ( T. Sugimoto et al., Molecular cloning and functional expression of V1b receptor gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research; T. Saito, K. Kurosawa and S. Yoshida, ed., Elsevier Science, 1995, 409413 ).
  • cholecystokinin gastrin
  • secretin T. Sugimoto et al., Molecular cloning and functional expression of V1b receptor gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research; T. Saito, K. Kurosawa and S. Yoshida, ed., Elsevier Science, 1995, 409413 ).
  • 1,3-Dihydro- 2H- indol-2-one derivatives have been described in certain patent applications as ligands for the arginine-vasopressin and / or oxytocin receptors: mention may be made of the patents WO 93/15051 , EP 636608 , EP 636609 , WO 97/15556 , WO 98/25901 , WO 01/55130 , WO 01/55134 , WO 01/64668 , WO 01/98295 , WO 03/008407 , WO 06/080574 , WO 08/025735 .
  • the compounds of formula (A) have an affinity for the receptors in general of vasopressin and / or oxytocin.
  • this application does not describe any example in which R II is in the position of phenyl and represents a methoxy radical and R IV is still linked in position -3- of the indol-2-one ring by a nitrogen atom .
  • the ⁇ compound has a good affinity for human V 1a receptors of AVP, but also for human V 2 V AV receptors and oxytocin receptors; it is therefore not selective for human V 1a receptors of AVP as well as for human V 1b receptors of AVP.
  • the ⁇ compound has a good affinity for human V 1a receptors of AVP, but also for human V 2 V AV receptors; it is therefore not selective for human V 1a receptors of AVP as well as for human V 1b receptors of AVP.
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful for purifying or isolating the compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) may exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
  • the N-oxides of compounds containing an amine are also part of the invention.
  • halogen atom is meant a bromine, chlorine, fluorine or iodine atom.
  • (C 1 -C 3 ) alkyl or (C 1 -C 4 ) alkyl is meant a linear or branched alkyl radical of one to three carbon atoms or of one to four carbon atoms, such as the methyl radical.
  • (C 1 -C 5 ) alkylene is meant a divalent radical of one to five carbon atoms such as the methylene, ethylene, trimethylene, tetramethylene radical or the pentamethylene radical.
  • (C 1 -C 4 ) alkoxy is meant a linear or branched alkoxy radical of one to four carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert -butoxy.
  • (C 3 -C 5 ) cycloalkyl is meant a cyclopropyl, cyclobutyl or cyclopentyl radical.
  • saturated or unsaturated 3 or 10-membered heterocyclic radical means a fused or bridged mono, di or tricyclic non-aromatic heterocyclic radical which may contain a second heteroatom such as nitrogen, oxygen or sulfur.
  • radicals include in particular the following radicals: 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 1-hexahydroazepinyl, 4-morpholinyl, 4-thiomorpholinyl, 2-azabicyclo [2.2.2] oct 5-en-2-yl, 2-methyl-2-azoniabicyclo [2.2.2] oct-5-en-2-yl, 2-azaadamant-2-yl, 1,2,3,6-tetrahydropyridine 1-yl, 2-azabicyclo [2.2.1] heptan-2-yl, 2-aza-bicyclo [2.2.2] octan-2-yl, 1-azoniabicyclo [
  • protecting group Pg is understood to mean a group that makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function. at the end of synthesis.
  • Examples of protecting groups as well as methods of protection and deprotection are given in "Protective Group in Organic Synthesis", Green et al., 4th Edition, John Wiley & Sons, Inc., New York, 2007 .
  • leaving group is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure from an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
  • Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of starting groups as well as references for their preparation are given in "Advanced Organic Chemistry," MB Smith and J. March, 6th Edition, Wiley Interscience, 2007, p.496-501 .
  • the compound of formula (I) is converted into one of its salts with inorganic or organic acids.
  • the reaction is carried out in the presence of a strong base such as a metal hydride such as sodium hydride or an alkali metal alcoholate such as potassium tert-butoxide, in an anhydrous solvent such as N, N-dimethylformamide or tetrahydrofuran and at a temperature between -70 ° C and + 60 ° C.
  • a strong base such as a metal hydride such as sodium hydride or an alkali metal alcoholate such as potassium tert-butoxide
  • an anhydrous solvent such as N, N-dimethylformamide or tetrahydrofuran
  • the compound of formula (I) is converted into one of its salts with inorganic or organic acids.
  • the reaction is carried out in the presence of an alkali metal carbonate such as sodium carbonate and in the presence of an alkali metal halide such as sodium iodide, in a solvent such as acetonitrile or N, N-dimethylformamide and at a temperature between room temperature and the reflux temperature of the solvent.
  • an alkali metal carbonate such as sodium carbonate
  • an alkali metal halide such as sodium iodide
  • the compounds of formula (I) thus obtained may subsequently be separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography.
  • the compounds of formula (II) are prepared by reaction of a 1,3-dihydro- 2H- indol-2-one compound of formula: in which R 2 , R 3 , R 4 and R 5 are as defined for a compound of formula (I) with a compound of formula: ZXR 1 (VII) in which X and R 1 are as defined for a compound of formula (I) and Z represents a leaving group such as a halogen atom, preferably iodine or bromine, or a methanesulfonate or p-toluene group sulfonate.
  • the reaction is carried out in the presence of a strong base such as an alkali metal alkoxide such as potassium tert- butoxide in a solvent such as tetrahydrofuran or N, N-dimethylformamide and at a temperature between -50 ° C and ambient temperature.
  • a strong base such as an alkali metal alkoxide such as potassium tert- butoxide
  • a solvent such as tetrahydrofuran or N, N-dimethylformamide
  • the compounds of formula (II) can also be prepared by reacting a compound of formula: in which R 2 , R 3 , R 4 and R 5 are as defined for a compound of formula (I) and Z represents a leaving group as previously described with a compound of formula R 1 H (V).
  • the reaction is carried out according to the operating conditions described above for the reaction of a compound of formula (IV) with a compound of formula (V).
  • the compounds of formula (III) are commercial, known or prepared by known methods such as those described in US Pat. EP 0 469 984 B and WO 95/18105 .
  • the compounds of formula (III) can be prepared by halogenation of the corresponding benzenesulphonic acids or their salts, for example their sodium or potassium salts.
  • the reaction is carried out in the presence of a halogenating agent such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, without a solvent or in a solvent such as a halogenated hydrocarbon or N, N-dimethylformamide and at a temperature between -10 ° C and 200 ° C.
  • the compounds of formula (III) can also be prepared by reacting chlorosulfonic acid with a compound of formula: wherein R 6 and R 7 are as defined for a compound of formula (I). The reaction is carried out according to the procedures described in Chlorosulfonic Acid; RJ Cremlyn; The Royal Society of Chemistry, 2002 .
  • the compounds of formula (IV) are prepared by reaction of a compound of formula: in which X, R 2 , R 3 , R 4 and R 5 are as defined for a compound of formula (I) and Z represents a leaving group as previously described with a compound of formula (III).
  • the reaction is carried out according to the operating conditions described above for the reaction of a compound of formula (II) with a compound of formula (III).
  • the compounds of formula (V) are commercial, known or prepared according to methods known to those skilled in the art.
  • the compounds of formula (VI) are known and are prepared according to known methods, such as those described in WO 95/18105 or in WO 01/55130 , which use commercial isatine chemistry, known or prepared according to known methods as described by Katristzky et al. in "Advances in Heterocyclic Chemistry; Academic Press, 1975; Vol 18, pp 1-58 .
  • the direct precursor 3-hydroxyindolinones of the compounds (VI) are reduced by known methods which use reducing agents such as triethylsilane in trifluoroacetic acid or in the presence of Lewis acid such as boron trifluoride complex, diethyl ether ( Bioorg. Med. Chem. Lett. 175-178 ).
  • the compounds of formula (VI) can also be prepared according to SCHEME 1 below, in which R represents a (C 1 -C 4 ) alkyl.
  • the compounds of formula (VI) are obtained by cyclization of the amine of formula (XI) generated in situ by reduction of the nitro group of the compounds of formula (X).
  • the reaction is carried out in the presence of a metal such as tin or iron in acidic medium such as acetic acid, in a solvent such as methanol and at a temperature between room temperature and 100 ° C.
  • the compounds of formula (VII) are commercially available or prepared according to known methods.
  • the compounds of formula (VIII) are prepared by reaction of a compound of formula: in which R 2 , R 3 , R 4 and R 5 are as defined for a compound of formula (I) with a compound of formula: Hal-XZ (XII) wherein X, is as defined for a compound of formula (I), Z is as defined above and Hal represents a halogen atom.
  • the reaction is carried out in the presence of a strong base such as an alkali metal alkoxide such as potassium tert- butoxide in a solvent such as tetrahydrofuran or N, N-dimethylformamide and at a temperature between -50 ° C and ambient temperature.
  • a strong base such as an alkali metal alkoxide such as potassium tert- butoxide
  • a solvent such as tetrahydrofuran or N, N-dimethylformamide
  • the compounds of formula (IX) are known or are prepared according to known methods.
  • the compounds of formula (X) are prepared by reaction of compounds of formula: in which R 2 and R 3 are as defined for a compound of formula (I) with a compound of formula: wherein R 4 and R 5 are as defined for a compound of formula (I).
  • the reaction is carried out in the presence of a strong base such as an alkaline alkoxide such as potassium tert- butoxide or a metal hydride such as sodium hydride, in an anhydrous solvent such as N, N-dimethylformamide and at a temperature between -50 ° C and room temperature.
  • a strong base such as an alkaline alkoxide such as potassium tert- butoxide or a metal hydride such as sodium hydride
  • N-oxides of the compounds containing an amine are prepared according to the methods known to those skilled in the art by reaction of the amine with organic peracids such as peracetic, trifluoroperacetic acids, performic, perbenzoic acid or its derivatives such as 3-chloroperbenzoic acid, at temperatures between 0 ° C and 90 ° C, preferably at temperatures below 50 ° C.
  • organic peracids such as peracetic, trifluoroperacetic acids, performic, perbenzoic acid or its derivatives such as 3-chloroperbenzoic acid
  • optically pure compounds of formula (I) can also be prepared from an optically pure intermediate compound useful for the preparation of the compounds of formula (I) according to the techniques described in US Pat. WO 03/008407 .
  • the rotational powers are measured on a PERKIN-ELMER 241 polarimeter.
  • the solvent mixtures are quantified in volumetric ratio.
  • the compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry).
  • the molecular peak (MH + ) and the retention time (tr) are measured in minutes.
  • a solution of 0.46 g of the compound of Preparation 1.1 in 11 ml of DMF is cooled to -50 ° C. under an argon atmosphere, 0.19 g of potassium tert- butylate is added and the mixture is left stirring. raise the temperature to -20 ° C.
  • the reaction mixture is cooled to -50 ° C., a solution of 0.19 ml of 1-bromo-4-chlorobutane in 5 ml of DMF is added dropwise and the mixture is left stirring for 16 hours, allowing the temperature to rise to 10 ° C. .
  • a saturated solution of NH 4 Cl is added, extracted with AcOEt, the organic phase washed with water, dried over Na 2 SO 4 and the solvent evaporated in vacuo.
  • a mixture of 0.15 g of the dextrorotatory compound obtained in Preparation 2a.2, 0.14 ml of 1-methylpiperazine, 0.05 g of Na 2 CO 3 and 0.067 g of NaI is heated at 100 ° C. for 3 hours. in 2 ml of DMF.
  • the reaction mixture is cooled to 15 ° C., water is added, the mixture is extracted with AcOEt, the organic phase is washed with water and dried over Na 2 SO 4, and the solvent is evaporated off under vacuum.
  • the residue is chromatographed on silica gel, eluting with a gradient of DCM / MeOH (100/0 v / v) to 70/30 v / v.
  • the expected compound is obtained.
  • the compound is obtained using the procedure of Preparation 3.4 from 2- (trifluoromethyl) phenol.
  • the expected compound is obtained using the method described in J. Org. Chem., 2006, 71, 9580 .
  • a solution of 0.28 g of the compound of Preparation 2.1 in 10 ml of THF is cooled to -30 ° C., 0.073 g of potassium tert- butoxide is added and the mixture is left stirring, allowing the temperature to rise to 0 ° C.
  • the reaction mixture was cooled to -60 ° C, 0.147 g of the compound of Preparation 3.1 was added and left stirring overnight at 20 ° C.
  • the reaction mixture is hydrolyzed by addition of water, extracted with AcOEt, dried organic phase over Na 2 SO 4 and the solvent evaporated under vacuum. The expected compound is obtained.
  • the compound of the preceding step is taken up in a solution of 2N hydrochloric ether and left stirring for 16 hours at 20 ° C.
  • a solution of 0.17 g of the compound of Preparation 2.3 in 2 ml of THF is cooled to -30 ° C., 0.54 ml of 1 M potassium tert- butylate in solution in THF is added and the mixture is left stirring and allowed to rise. the temperature at 0 ° C.
  • the reaction mixture is cooled to -60 ° C, 0.127 g of commercial 4-isopropoxybenzenesulfonyl chloride is added and the mixture is stirred overnight at 20 ° C.
  • the reaction mixture is hydrolyzed by addition of water, extracted with AcOEt, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum.
  • a solution of 0.177 g of the compound of Preparation 2.5 in 3 ml of THF is cooled to -30 ° C., 0.48 ml of a 1M solution of potassium tert- butoxide in THF is added and the mixture is left stirring and left to stir. the temperature at 0 ° C.
  • the reaction mixture was cooled to -60 ° C, 0.112 g of 4-isopropoxybenzenesulfonyl chloride was added and left stirring overnight at 20 ° C.
  • the reaction mixture is hydrolyzed by addition of water, extracted with AcOEt, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum.
  • a solution of 0.128 g of the compound of Preparation 2.4 in 2 ml of THF is cooled to -30 ° C., 0.066 g of potassium tert-butoxide is added and the mixture is left stirring and the temperature is allowed to rise to 0 ° C.
  • the reaction mixture was cooled to -30 ° C, 0.09 g of 4-isopropoxybenzenesulfonyl chloride was added and left stirring overnight at 10 ° C.
  • the reaction mixture is hydrolyzed by addition of water, extracted with AcOEt, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM / MeOH mixture.
  • a solution of 0.128 g of the compound of Preparation 2.4 in 2 ml of THF is cooled to -30 ° C., 0.066 g of potassium tert-butoxide is added and the mixture is left stirring and the temperature is allowed to rise to 0 ° C.
  • the reaction mixture is cooled to -30 ° C, 0.097 g of 4-ethoxy-3-methoxybenzenesulfonyl chloride (described in Chem. Ber., 1906, 39, 2777 ) and left stirring overnight at 10 ° C.
  • the reaction mixture is hydrolyzed by addition of water, extracted with AcOEt, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum.
  • the compounds according to the invention have been the subject of pharmacological tests.
  • the affinity of the compounds of formula (I) according to the invention for the V 1a receptors of arginine-vasopressin was determined in vitro using the method described by M. Thibonnier et al., J. Biol. Chem., 1994, 269, 3304-3310 . This method consists of studying in vitro the displacement of tritiated arginine-vasopressin ([ 3 H] -AVP) at the V 1a receptors present on membrane or cell preparations carrying the rat or human V 1a receptors.
  • the compounds of formula (I) have an affinity for human arginine-vasopressin V 1a receptors with IC 50 (inhibitory concentration of 50% of tritiated arginine-vasopressin binding ([ 3 H] -AVP at its receptors)) generally below 10 nanomolar (10 -8 M) in the latter test.
  • the affinity of the compounds of formula (I) according to the invention for the V 1b receptors of arginine-vasopressin was determined in vitro using the method described by Y. de Keyser et al. in Febs Letters, 1994, 356, 215-220 . This method consists in studying in vitro the displacement of tritiated arginine-vasopressin ([ 3 H] -AVP) to V 1b receptors present on cell preparations carrying human V 1b receptors. In addition, some test compounds have an affinity for human V 1b receptors with IC 50 values of less than 30 nanomolar (3.10 -8 M) in the latter test.
  • the affinity of the compounds of formula (I) according to the invention for the V 2 receptors of vasopressin has also been studied (method described by M. Birnbaumer et al. in Nature (Lond.), 1992, 357, 333-335 ).
  • the test compounds have little or no affinity for human V 2 receptors with IC 50 greater than 10 -7 M.
  • the affinity of the compounds according to the invention for the oxytocin receptors was determined in an in vitro binding assay using the method described by J. Elands et al. in Eur. J. Pharmacol., 1987, 147, 197-207 .
  • This method consists in studying in vitro the displacement of a radioiodinated oxytocin analogue to oxytocin receptors in a membrane preparation of cells transfected with the human uterine oxytocin receptor.
  • test compounds have little or no affinity for human oxytocin receptors with IC 50 values generally greater than 10 -7 M.
  • TABLE XV illustrates the comparative pharmacological results of compounds Nos. 17, 38, 46, 107 and 108 according to the invention with the ⁇ and ⁇ compounds of the prior art on the various in-vitro tests measuring the affinity to human V 1a , V 1b , V 2 and oxytocin receptors. The results are expressed by the 50% inhibitory concentration (IC 50 ) nanomolar (nM).
  • the agonist or antagonist character of the compounds is determined in vitro in an intracellular calcium measurement test (FLIPR) on cells expressing human V1a receptors according to the general technique described in FIG. Sullivan et al, Methods Mol. Biol., 1999, 114, 125-133 , using 1 ⁇ M Fluo4 AM and in a platelet aggregation test induced on AVP on PRP (platelet rich plasma) according to the methodology described in J. Clin. Invest., 1993, 92, 224-231 .
  • the compounds are preincubated 30 minutes prior to the addition of arginine vasopressin to determine the agonist and antagonist properties of these molecules.
  • the IC 50's of the compounds according to the invention for V 1a receptors measured in these studies are low (less than 2.10 -8 M).
  • the compounds according to the invention can therefore be used for the preparation of medicaments, in particular antagonists of human V 1a receptors of arginine vasopressin and in addition for certain compounds of human V 1b receptors of AVP.
  • the invention relates to medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or a hydrate or a solvate of the compound of formula (I).
  • medicaments find use in therapy, and are advantageously useful in the disorders of the urogenital sphere, particularly in the obstetric and gynecological fields, especially as a tocolytic or uterine relaxant agent or for controlling uterine hyperactivity, the contractions of the uterus before the pregnancy has come to an end, to control prenatal work, or to control the preparatory work for delivery by caesarean section, to promote the growth of the fetus in-utero, to reduce stress and anoxia at the time of contractions, to resolve problems of infertility, fertility, birth control (especially veterinary use), control oestrus, weaning, transfer and embryo implantation during in vitro fertilization; treat endometriosis, dysmenorrhea, as well as stress or urgency urinary incontinence, benign prostatic hypertrophy, urination disorders, urogenital infections, urinary lithiasis and erectile dysfunction
  • vasopressin-dependent conditions such as cardiovascular conditions, such as hypertension, pulmonary hypertension, heart failure, myocardial infarction, or coronary vasospasm, in particular. particularly in the smoker, Raynaud's disease, unstable angina and PTCA (percutaneous transluminal coronary angioplasty), cardiac ischemia, disturbances of hemostasis, thrombosis; central nervous system conditions such as migraine, cerebral vasospasm, cerebral hemorrhage, trauma and cerebral edema, depression, anxiety, stress, emotional disorders, obsessive-compulsive disorder, panic attacks , psychotic states, aggression, memory problems, sleep disorders, cognitive disorders for example; renal system disorders such as renal vasospasm, necrosis of the renal cortex; nephrogenic diabetes insipidus; diabetic nephropathy; disorders of the gastric system such as gastric vasospasm, hepatocirrhosis, ulcers, path
  • the compounds according to the invention can also be used in the treatment of disorders of sexual behavior; in women, the compounds according to the invention can be used to treat primary and secondary dysmenorrhea, premature labor or endometriosis.
  • the compounds according to the invention can also be used in the treatment of cancers such as small cell lung cancers or mammary cancers; hyponatremic encephalopathies; pulmonary syndrome, Meniere's disease; ocular hypertension, glaucoma, cataracts; obesity; type I and II diabetes; atherosclerosis; metabolic syndrome; hyperlipidemia; insulin resistance; hypertriglyceridemia; in post-operative treatments, especially after abdominal surgery; autism; hypercortisolemia; hyperaldosteronemia; pheochromocytomas; Cushing's syndrome; pre-season; disorders of micturation; premature ejaculation.
  • cancers such as small cell lung cancers or mammary cancers; hyponatremic encephalopathies; pulmonary syndrome, Meniere's disease; ocular
  • the compounds according to the invention can also be used in the treatment or prevention of all pathologies resulting from stress such as fatigue and its syndromes, ACTH-dependent disorders, cardiac disorders, pain, changes in gastric emptying, faecal excretion (colitis, irritable bowel syndrome, Crohn's disease), acid secretion, hyperglycemia, immunosuppression, inflammatory processes (rheumatoid arthritis and osteoarthritis), multiple infections, septic shock, cancers , asthma, psoriasis, allergies and various neuropsychiatric disorders such as anorexia nervosa, bulimia nervosa, mood disorders, depression, anxiety, sleep disorders, panic states, phobias, obsession, pain perception disorders (fibromyalgia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dependence this to a substance (alcohol or drug), weaning, hemorrhagic stress, muscle spasm, hypoglycemia.
  • the compounds according to the invention can also be used as psychostimulants, causing the increase of awakening, the emotional reactivity to the environment and facilitating adaptation.
  • the compounds according to the present invention can finally be used in healing, in analgesia, in anxiolysis, in the prevention of pain, in the prevention of anxiety, depression, schizophrenia, autism, obsessive-compulsive syndromes, in maternal behavior (facilitating recognition and acceptance of the mother by the child) and social, memory; regulation of food and drink intake, drug dependence, withdrawal and sexual motivation; hypertension, hyponatremia, heart failure, atherosclerosis, angiogenesis, tumor proliferation, Kaposi's sarcoma, regulate fat storage by adipocyte, control hyperlipidemia, triglyceride and metabolic syndrome .
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a solvate or hydrate of said compound, as well as at least one pharmaceutically acceptable excipient.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its Any salt, solvate or hydrate may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions
  • sublingual, oral, intratracheal intraocular, intranasal forms of administration by inhalation
  • topical, transdermal, subcutaneous, intramuscular or intravenous administration forms rectal administration forms and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol: 223.75 mg Croscarmellose sodium: 6.0 mg Corn starch : 15.0 mg Hydroxypropyl methylcellulose: 2.25 mg Magnesium stearate: 3.0 mg
  • the dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or more doses, preferably 0.02 to 50 mg / kg.
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
  • the present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or hydrates or solvates for the preparation of a medicament for the treatment of the pathologies indicated above.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Reproductive Health (AREA)
  • Ophthalmology & Optometry (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gynecology & Obstetrics (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Obesity (AREA)
  • Pregnancy & Childbirth (AREA)
  • Addiction (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Dermatology (AREA)
  • Psychology (AREA)
  • Rheumatology (AREA)

Claims (10)

  1. Verbindung der Formel (I):
    Figure imgb0219
     mit den folgenden Bedeutungen:
    - X bedeutet einen zweiwertigen (C1-C5)Alkylenrest, der unsubstituiert oder einfach oder mehrfach an einem Kohlenstoffatom durch ein Fluoratom oder (C1-C3)Alkyl substituiert ist;
    - R1 bedeutet:
    - eine -NR8R9-Gruppe;
    - einen Piperidin-4-ylrest oder einen Piperidin-3-ylrest, der unsubstituiert oder einfach oder mehrfach durch ein (C1-C4)Alkyl, ein (C3-C5)Cycloalkyl substituiert ist, wobei die Kohlenstoffatome auch durch ein oder mehrere Fluoratome substituiert sein können;
    - R2 bedeutet ein Wasserstoffatom, eine Alk-Gruppe, eine OAlk-Gruppe;
    - R3 bedeutet Methoxy;
    - R4 bedeutet ein Wasserstoffatom, ein Halogenatom, eine Alk-Gruppe, ein Hydroxyl, eine OAlk-Gruppe;
    - R5 bedeutet ein Wasserstoffatom, ein Halogenatom, eine Alk-Gruppe, ein Hydroxyl, eine OAlk-Gruppe, eine -CO2Alk-Gruppe, einen -CH2OH-Rest;
    - R6 bedeutet ein Wasserstoffatom, eine Alk-Gruppe, ein Hydroxyl, eine OAlk-Gruppe, ein (C3-C5)Cycloalkyloxy, eine -NR10CONR11R12-Gruppe;
    - R7 bedeutet ein Wasserstoffatom, ein Halogenatom, eine Alk-Gruppe, ein Hydroxyl, eine OAlk-Gruppe;
    - oder R7 befindet sich in der -3-Stellung des Phenyls und bedeutet zusammen mit R6 einen Trimethylenrest;
    - R8 und R9 bedeuten jeweils unabhängig voneinander ein Wasserstoffatom oder ein (C1-C4)Alkyl;
    - oder R8 und R9 bilden gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen gesättigten oder ungesättigten heterocyclischen Ring mit 3 bis 10 Ringgliedern, wobei der heterocyclische Rest unsubstituiert oder einfach oder mehrfach durch ein Amino, ein Dimethylamino, ein Hydroxyl, eine Alk-Gruppe, ein (C3-C5)Cycloalkyl, eine OAlk-Gruppe, einen -SO2-Alk-Rest substituiert ist, wobei die Kohlenstoffatome auch durch ein oder mehrere Fluoratome substituiert sein können;
    - R10 bedeutet ein Wasserstoffatom oder ein (C1-C4)Alkyl;
    - R11 und R12 bedeuten jeweils unabhängig voneinander ein Wasserstoffatom oder ein (C1-C4)Alkyl;
    - Alk bedeutet ein (C1-C4)Alkyl, das unsubstituiert oder einfach oder mehrfach durch ein Fluoratom substituiert ist;
    als Base oder als Säureadditionssalz sowie als Hydrate oder Solvate.
  2. Verbindungen der Formel (I) nach Anspruch 1, mit den folgenden Bedeutungen:
    - X bedeutet einen zweiwertigen (C1-C5)Alkylenrest, der unsubstituiert oder einfach oder mehrfach an einem Kohlenstoffatom durch ein Fluoratom oder durch ein (C1-C3)Alkyl substituiert ist;
    - R1 bedeutet:
    • eine -NR8R9-Gruppe;
    • einen Piperidin-4-ylrest oder einen Piperidin-3-ylrest, der unsubstituiert oder durch Methyl substituiert ist;
    - R2 bedeutet ein Halogenatom, Methyl, Methoxy;
    - R3 bedeutet Methoxy;
    - R4 bedeutet ein Wasserstoffatom, ein Fluoratom, Methyl oder Methoxy;
    - R5 bedeutet ein Wasserstoffatom, ein Halogenatom, eine -CO2Alk-Gruppe, einen -CH2OH-Rest;
    - R6 bedeutet ein Wasserstoffatom, eine Alk-Gruppe, eine OAlk-Gruppe, Hydroxyl, Cyclopentyloxy, eine -NHCON(Et)2-Gruppe;
    - R7 bedeutet ein Wasserstoffatom, ein Halogenatom, Methyl, Methoxy, einen CF3-Rest;
    - oder R7 steht in -3-Stellung des Phenyls und bildet gemeinsam mit R6 einen Trimethylenrest;
    - R8 und R9 bedeuten jeweils Methyl;
    - oder R8 und R9 bilden gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen heterocyclischen Rest, der aus der folgenden Reihe ausgewählt ist: Pyrrolidin-1-yl, Piperidin-1-yl, Morpholin-4-yl, Piperazin-1-yl, 1,4-Diazepan-1-yl, 2,5-Diazabicyclo[2.2.1]hept-2-yl, 3,8-Diazabicyclo[3.2.1]oct-3-yl, 2,5-Diazabicyclo[2.2.2]oct-2-yl, 1,4-Diazabicyclo[3.2.1]oct-4-yl, Hexahydropyrrolo[1,2-a]pyrazin-2-(1H)-yl, Octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, wobei der heterocyclische Rest unsubstituiert oder einfach oder zweifach durch ein Fluoratom, Amino, Dimethylamino, Hydroxyl, eine Alk-Gruppe, Cyclobutyl, einen -SO2Me-Rest substituiert ist;
    - Alk bedeutet ein (C1-C4)Alkyl, das unsubstituiert oder einfach oder mehrfach durch ein Fluoratom substituiert ist;
    als Base oder als Säureadditionssalz, sowie als Hydrat oder Solvat.
  3. Verbindungen der Formel (I) nach Anspruch 1, mit den folgenden Bedeutungen:
    - X bedeutet einen zweiwertigen (C1-C5)Alkylenrest;
    - R1 bedeutet:
    • Dimethylamino, 3-Aminopyrrolidin-1-yl, 3-Dimethylaminopyrrolidin-1-yl, Piperidinyl-1-yl, 3,3-Difluorpiperidin-1-yl, 4,4-Difluorpiperidin-1-yl, 4-Hydroxypiperidin-1-yl, Morpholin-4-yl, 4-Methylpiperazin-1-yl, Piperazin-1-yl, 4-Ethylpiperazin-1-yl, 1,4-Diazepan-1-yl, 2,5-Diazabicyclo[2.2.1]hept-2-yl, 4-Isopropylpiperazin-1-yl, 3-Methylpiperazin-1-yl, 3,4-Dimethylpiperazin-1-yl, 4-Cyclobutylpiperazin-1-yl, 5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 3,5-Dimethylpiperazin-1-yl, 4-Methyl-1,4-diazepan-1-yl, 8-Methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 2,6-Dimethylpiperazin-1-yl, 3-Isopropylpiperazin-1-yl, 2,2-Dimethylpiperazin-1-yl, 2,5-Diazabicyclo[2.2.2]oct-2-yl, 2,5-Dimethylpiperazin-1-yl, 2,2,4-Trimethylpiperazin-1-yl, 1,4-Diazabicyclo[3.2.1]oct-4-yl, 2-Isopropylpiperazin-1-yl, Hexhydropyrrolo[1.2-a]pyrazin-2-(1H)yl, Octahydro-2H-pyrido[1.2-a]pyrazin-2-yl, 3-Trifluormethylpiperazin-1-yl, 4-Methylsulfonylpiperazin-1-yl, 4-(Dimethylamino)piperidin-1-yl,
    • Piperidin-4-yl, 1-Methylpiperidin-4-yl, 1-Methylpiperidin-3-yl, Piperidin-3-yl;
    - R2 bedeutet ein Chloratom, Fluoratom, Bromatom, Methyl, Methoxy;
    - R3 bedeutet Methoxy;
    - R4 bedeutet ein Wasserstoffatom, ein Fluoratom, Methyl, Methoxy;
    - R5 bedeutet ein Wasserstoffatom, 3-Chlor-, 5-Fluor-, 6-Fluor-, 5-Methoxycarbonyl, 5-Hydroxymethyl;
    - R6 bedeutet ein Wasserstoffatom, Methyl, Isopropyl, Methoxy, Ethoxy, Isopropoxy, Butyloxy, tert.-Butyloxy, Cyclopentyloxy, 1,1,2,2-Tetrafluorethyloxy, 2,2-Diethylureido, Difluormethoxy, Trifluormethoxy, Hydroxy;
    - R7 bedeutet ein Wasserstoffatom, 3-Methyl, 2-Methoxy, 3-Methoxy, 3-Fluor-, 3-Chlor-, 3-CF3;
    - oder R7 befindet sich in -3-Stellung des Phenyls und bildet gemeinsam mit R6 einen Trimethylenrest;
    als Base oder als Säureadditionssalz sowie als Hydratsolvat.
  4. Verbindung nach Anspruch 1 der Formel (I), mit den folgenden Bedeutungen:
    - X bedeutet einen zweiwertigen Trimethylen- oder Pentamethylenrest;
    - R1 bedeutet:
    • Dimethylamino, 3-Aminopyrrolidin-1-yl, Piperidin-1-yl, 4,4-Difluorpiperidin-1-yl, 4-Hydroxypiperidin-1-yl, 4-(Dimethylamino)piperidin-1-yl, Morpholin-4-yl, 4-Methylpiperazin-1-yl, Piperazin-1-yl, 3,4-Dimethylpiperazin-1-yl, 5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 4-Methyl-1,4-diazepan-1-yl, 8-Methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 1,4-Diazabicyclo[3.2.1]oct-4-yl;
    • Piperidin-4-yl;
    - R2 bedeutet ein Chlor-, Fluor-, Bromatom oder Methyl;
    - R3 bedeutet Methoxy;
    - R4 bedeutet ein Wasserstoffatom oder ein Fluoratom;
    - R5 bedeutet ein Wasserstoffatom, 5-Methoxycarbonyl, 5-Hydroxymethyl;
    - R6 bedeutet ein Wasserstoffatom, Methyl, Methoxy, Isopropoxy, Ethoxy, Butyloxy, 1,1,2,2-Tetrafluorethyloxy, 2,2-Diethylureido, Difluormethoxy, Trifluormethoxy, Hydroxyl;
    - R7 bedeutet ein Wasserstoffatom, 2-Methoxy, 3-Methoxy, 3-Methyl, 3-Fluor;
    als Base oder als Säureadditionssalz sowie als Hydrat oder Solvat.
  5. Verbindung nach Anspruch 1 der Formel (I), ausgewählt aus der folgenden Reihe:
    - 5-Chlor-1-[(2,4-Dimethoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperidin-4-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(2,4-Dimethoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperidin-4-ylpropyl)-1,3-dihydro-2H-indol-2-on, linksdrehendes Isomer;
    - 5-Chlor-3-[3-(dimethylamino)propyl]-3-(2-fluorphenyl)-1-[(4-isopropoxyphenyl)sulfonyl]-6-methoxy-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 3-{3-[(3R)-3-Aminopyrrolidin-1-yl]propyl}-5-chlor-3-(2-fluorphenyl)-1-[(4-isopropoxyphenyl)sulfonyl]-6-methoxy-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 3-{3-[(3S)-3-Aminopyrrolidin-1-yl]propyl}-5-chlor-3-(2-fluorphenyl)-1-[(4-isopropoxyphenyl)sulfonyl]-6-methoxy-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 3-{3-[(3R)-3-Aminopyrrolidin-1-yl]propyl}-5-chlor-1-[(4-ethoxy-3-methoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 3-{3-[(3S)-3-Aminopyrrolidin-1-yl]propyl}-5-chlor-1-[(4-ethoxy-3-methoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperidin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-[3-(4,4-difluorpiperidin-1-yl)propyl]-1-[(4-ethoxy-3-methoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(4-ethoxy-3-methoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-3-[3-(4-hydroxypiperidin-1-yl)propyl]-6-methoxy-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(4-ethoxy-3-methoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-morpholin-4-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-1H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-1-[(4-isopropoxyphenyl)sulfonyl]-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(4-ethoxy-3-methoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtdrehendes Isomer;
    - 5-Chlor-1-[(3,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-1-[(4-isopropoxyphenyl)sulfonyl]-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(4-ethoxy-3-methoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(3,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(3,4-dimethylphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-6-methoxy-1-[(4-methoxy-3-methylphenyl)sulfonyl]-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on;
    - 5-Chlor-1-[(4-ethoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-[(4-ethoxy-3-methylphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on;
    - 5-Chlor-1-{[4-(difluormethoxy)phenyl]sulfonyl}-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1-{[4-(trifluormethoxy)phenyl]sulfonyl}-1,3-dihydro-2H-indol-2-on, rechtdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-6-methoxy-1-(phenylsulfonyl)-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtdrehendes Isomer;
    - 5-Chlor-1-(2,3-dihydro-1H-inden-5-ylsulfonyl)-3-(2-fluorphenyl)-6-methoxy-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-1-{[3-fluor-4-(1-methylethoxy)phenyl]sulfonyl}-3-(2-fluorphenyl)-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1-{[4-(1,1,2,2-tetrafluorethoxy)phenyl]sulfonyl}-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 3-(2-Fluorphenyl)-6-methoxy-5-methyl-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Fluor-3-(2-fluorphenyl)-6-methoxy-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Brom-3-(2-fluorphenyl)-6-methoxy-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 3-[4-({3-[3-(Dimethylamino)propyl]-3-(2-fluorphenyl)-6-methoxy-5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl}sulfonyl)-2-fluorphenyl]-l,l-diethylharnstoff, rechtsdrehendes Isomer;
    - 3-[4-({3-[3-(Dimethylamino)propyl]-3-(2-fluorphenyl)-6-methoxy-5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl}sulfonyl)-2-methylphenyl]-1,1-diethylharnstoff, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-6-methoxy-3-[3-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)propyl]-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-6-methoxy-3-[3-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)propyl]-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-1-[(4-hydroxyphenyl)sulfonyl]-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-6-methoxy-3-[3-(4-methyl-1,4-diazepan-1-yl)propyl]-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-(2-fluorphenyl)-6-methoxy-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-3-(5-piperidin-1-ylpentyl)-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-[5-(dimethylamino)pentyl]-3-(2-fluorphenyl)-6-methoxy-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-{3-[(3S)-3,4-dimethylpiperazin-1-yl]propyl}-3-(2-fluorphenyl)-6-methoxy-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-6-methoxy-1-{[4-(1-methylethoxy)-phenyl]sulfonyl}-3-[3-(4-methylpiperazin-1-yl)propyl]-3-phenyl-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-{3-[(5S)-1,4-diazabicyclo[3.2.1]oct-4-yl]propyl}-3-(2-fluorphenyl)-6-methoxy-1-{[4-(1-methylethoxy)phenyl]sulfonyl}-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 1-[(4-Butoxyphenyl)sulfonyl]-5-chlor-3-(2-fluorphenyl)-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on, rechtsdrehendes Isomer;
    - 5-Chlor-3-[3-[4-(dimethylamino)piperidin-1-yl]propyl]-3-(2-fluorphenyl)-1-[(4-isopropoxyphenyl)sulfonyl]-6-methoxy-1,3-dihydro-2H-indol-2-on;
    - 1-[(3-Fluor-4-isopropoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-5,6-dimethoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on;
    - 5-Fluor-1-[(3-fluor-4-isopropoxyphenyl)sulfonyl]-3-(2-fluorphenyl)-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on;
    - 3-(2-Fluorphenyl)-5,6-dimethoxy-1-[(4-methoxy-3-methylphenyl)sulfonyl]-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on;
    - Methyl-3-[5-Chlor-1-[(4-isopropoxyphenyl)sulfonyl]-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluorbenzoat
    - 5-Chlor-3-[2-fluor-5-(hydroxymethyl)phenyl]-1-[(4-isopropoxyphenyl)sulfonyl]-6-methoxy-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-dihydro-2H-indol-2-on;
    als Base oder als Säureadditionssalze sowie als Hydrate oder Solvate.
  6. Verfahren zur Herstellung von Verbindungen der Formel (I) nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass man:
    eine Verbindung der Formel:
    Figure imgb0220
     in der X, R1, R2, R3, R4 und R5 wie für eine Verbindung der Formel (I) in Anspruch 1 definiert sind, mit einem Sulfonylhalogenid der Formel:
    Figure imgb0221
     in der R6 und R7 wie für eine Verbindung der Formel (I) in Anspruch 1 definiert sind und Hal ein Halogenatom bedeutet, in Gegenwart einer Base umsetzt.
  7. Verfahren zur Herstellung von Verbindungen von Formel (I) nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass man:
    eine Verbindung der Formel
    Figure imgb0222
     in der X, R2, R3, R4, R5, R6 und R7 wie für eine Verbindung der Formel (I) in Anspruch 1 definiert sind und Z eine Abgangsgruppe, ausgewählt aus der Reihe Halogenatom oder Methansulfonatgruppe oder p-Toluolsulfonatgruppe bedeutet, mit einer Verbindung der Formel:

            R1-H     (V)

    in der R1 wie für eine Verbindung der Formel (I) in Anspruch 1 definiert ist, umsetzt.
  8. Arzneimittel, dadurch gekennzeichnet, dass es eine Verbindung der Formel (I) nach einem der Ansprüche 1 bis 5 oder ein Additionssalz dieser Verbindung mit einer pharmazeutisch unbedenklichen Säure oder ein Hydrat oder ein Solvat der Verbindung der Formel (I) umfasst.
  9. Pharmazeutische Zusammensetzung, dadurch gekennzeichnet, dass sie eine Verbindung der Formel (I) nach einem der Ansprüche 1 bis 5 oder ein pharmazeutisch unbedenkliches Salz, ein Hydrat oder ein Solvat dieser Verbindung sowie mindestens einen pharmazeutisch unbedenklichen Grundstoff umfasst.
  10. Verwendung einer Verbindung der Formel (I) nach einem der Ansprüche 1 bis 5 für die Herstellung eines Arzneimittels zur Behandlung und Vorbeugung von Hypertonie, pulmonaler Hypertonie, Herzinsuffizienz, Myokardinfarkt, koronarem Vasospasmus, insbesondere bei Rauchern, Raynaud-Krankheit, instabiler Angina und PTCA (englisch: Percutaneous Transluminal Coronary Angioplasty), zerebralem Vasospasmus, Hirnblutung, Hirntraumen und -ödemen, Depression, Angstzuständen, Stress, emotionalen Problemen, Gedächtnisproblemen, Schlafproblemen, diabetischer Nephropathie, Karzinomen wie kleinzelligem Lungenkarzinom oder Mammakarzinomen; Arteriosklerose; metabolischem Syndrom; Hyperlipidämie; Insulinresistenz, Hypertriglyceridämie, Hypercortisolämie, Hyperaldosteronämie, Phäochromocytomen, Cushing-Syndrom, Colitis, Reizkolon, Morbus Chron, Schmerzen (Fibromyalgie), neurodegenerativen Erkrankungen (Morbus Alzheimer, Morbus Parkinson, Huntington-Chorea), Substanzabhängigkeit (Alkohol oder Drogen); als Tokolytikum oder als Uterusrelaxant oder für die Kontrolle von Uterushyperaktivität, von vorzeitigen Wehen, zur Förderung des Fötalwachstums in utero, zum Behandeln von Endometriose, von Dysmenorrhö und von Erektionsstörungen.
EP09721627A 2008-02-19 2009-02-18 Neuartige 3-aminoalkyl-1,3-dihydro-2h-indol-2-on-derivate, ihre herstellung und therapeutische verwendung Active EP2265582B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0800866A FR2927625B1 (fr) 2008-02-19 2008-02-19 Nouveaux derives de 3-aminoalkyl-1,3-dihydro-2h-indol-2-one, leur preparation et leur application en therapeutique
PCT/FR2009/000179 WO2009115685A1 (fr) 2008-02-19 2009-02-18 Nouveaux derives de 3-aminoalkyl-1,3-dihydro-2h-indol-2-one, leur preparation et leur application en therapeutique.

Publications (2)

Publication Number Publication Date
EP2265582A1 EP2265582A1 (de) 2010-12-29
EP2265582B1 true EP2265582B1 (de) 2012-01-04

Family

ID=39874092

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09721627A Active EP2265582B1 (de) 2008-02-19 2009-02-18 Neuartige 3-aminoalkyl-1,3-dihydro-2h-indol-2-on-derivate, ihre herstellung und therapeutische verwendung

Country Status (15)

Country Link
US (1) US8362067B2 (de)
EP (1) EP2265582B1 (de)
JP (1) JP5602639B2 (de)
KR (1) KR20100126401A (de)
CN (1) CN102015642A (de)
AR (1) AR070438A1 (de)
AT (1) ATE540023T1 (de)
AU (1) AU2009227111A1 (de)
BR (1) BRPI0907578A2 (de)
CA (1) CA2716035A1 (de)
FR (1) FR2927625B1 (de)
IL (1) IL207629A0 (de)
MX (1) MX2010009092A (de)
RU (1) RU2010138575A (de)
WO (1) WO2009115685A1 (de)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2927625B1 (fr) 2008-02-19 2010-03-12 Sanofi Aventis Nouveaux derives de 3-aminoalkyl-1,3-dihydro-2h-indol-2-one, leur preparation et leur application en therapeutique
CN103269584B (zh) 2010-07-01 2017-05-03 阿泽凡药物公司 用于治疗创伤后应激障碍的方法
KR20160130853A (ko) * 2014-03-28 2016-11-14 아제반 파마슈티칼스, 인코퍼레이티드 신경변성 질환을 치료하기 조성물 및 방법
CN104592088B (zh) * 2015-01-05 2019-01-01 内蒙古工业大学 月桂酸催化制备3-胺烷基吲哚的方法
CN105061290B (zh) * 2015-08-28 2017-11-10 福建品派包装有限公司 一种吲哚酮类化合物的合成方法
CN105061291B (zh) * 2015-09-08 2017-08-04 江俞 一种杂稠环取代的吲哚酮类化合物的合成方法
AU2018333051B2 (en) 2017-09-15 2024-03-21 Azevan Pharmaceuticals, Inc. Compositions and methods for treating brain injury
CN108675945B (zh) * 2018-06-22 2020-09-22 湖南科技大学 ((2-羟基苄基)胺基)苯基脲类化合物及其制备方法和用途

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU550845B2 (en) 1981-03-30 1986-04-10 Sumitomo Chemical Company, Limited Tetrahydrophthalimides and their starting compounds
FR2665441B1 (fr) 1990-07-31 1992-12-04 Sanofi Sa Derives de la n-sulfonyl indoline, leur preparation, les compositions pharmaceutiques en contenant.
FR2686878B1 (fr) * 1992-01-30 1995-06-30 Sanofi Elf Derives du n-sulfonyl oxo-2 indole, leur preparation, les compositions pharmaceutiques en contenant.
FR2708606B1 (fr) 1993-07-30 1995-10-27 Sanofi Sa Dérivés du N-phénylalkylindol-2-one, leur préparation, les compositions pharmaceutiques en contenant.
FR2714378B1 (fr) * 1993-12-24 1996-03-15 Sanofi Sa Dérivés de l'indol-2-one substitués en 3 par un groupe azoté, leur préparation, les compositions pharmaceutiques en contenant.
US5618633A (en) * 1994-07-12 1997-04-08 Precision Castparts Corporation Honeycomb casting
FR2740136B1 (fr) 1995-10-24 1998-01-09 Sanofi Sa Derives d'indolin-2-one, procede pour leur preparation et les compositions pharmaceutiques les contenant
FR2757157B1 (fr) 1996-12-13 1999-12-31 Sanofi Sa Derives d'indolin-2-one, procede pour leur preparation et compositions pharmaceutiques les contenant
FR2804114B1 (fr) * 2000-01-25 2002-03-08 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2804115B1 (fr) * 2000-01-25 2002-03-08 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2805536B1 (fr) * 2000-02-25 2002-08-23 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
US20030100772A1 (en) 2000-03-02 2003-05-29 Etsuo Ohshima Oxygen-containing heterocyclic compounds
FR2810320B1 (fr) * 2000-06-19 2002-08-23 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2827604B1 (fr) * 2001-07-17 2003-09-19 Sanofi Synthelabo Nouveaux derives de 1-phenylsulfonyl-1,3-dihydro-2h-indol-2- one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
US20050070718A1 (en) * 2003-09-30 2005-03-31 Abbott Gmbh & Co. Kg Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
DE102004033834A1 (de) * 2004-07-13 2006-02-02 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate und diese enthaltende Arzneimittel
US8030499B2 (en) 2005-01-28 2011-10-04 Taisho Pharmaceutical Co., Ltd. 1,3-dihydro-2H-indole-2-one compound and pyrrolidine-2-one compound fused with aromatic heterocycle
WO2006100082A2 (de) * 2005-03-24 2006-09-28 Abbott Gmbh & Co. Kg Substituierte oxindol-derivate, diese enthaltende arzneimittel und deren verwendung
DE102006040915A1 (de) 2006-08-26 2008-03-20 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung
FR2927625B1 (fr) 2008-02-19 2010-03-12 Sanofi Aventis Nouveaux derives de 3-aminoalkyl-1,3-dihydro-2h-indol-2-one, leur preparation et leur application en therapeutique

Also Published As

Publication number Publication date
CN102015642A (zh) 2011-04-13
RU2010138575A (ru) 2012-03-27
AU2009227111A1 (en) 2009-09-24
KR20100126401A (ko) 2010-12-01
BRPI0907578A2 (pt) 2019-09-24
IL207629A0 (en) 2010-12-30
EP2265582A1 (de) 2010-12-29
JP2011512389A (ja) 2011-04-21
FR2927625A1 (fr) 2009-08-21
US8362067B2 (en) 2013-01-29
FR2927625B1 (fr) 2010-03-12
JP5602639B2 (ja) 2014-10-08
WO2009115685A1 (fr) 2009-09-24
ATE540023T1 (de) 2012-01-15
US20110059955A1 (en) 2011-03-10
CA2716035A1 (fr) 2009-09-24
AR070438A1 (es) 2010-04-07
MX2010009092A (es) 2011-09-21

Similar Documents

Publication Publication Date Title
EP1255751B1 (de) 1,3-dihydro-2h-indol-2-on derivate und deren verwendung als liganden der arginin-vasopressin rezeptoren v1b oder v1b und v1a
EP2265582B1 (de) Neuartige 3-aminoalkyl-1,3-dihydro-2h-indol-2-on-derivate, ihre herstellung und therapeutische verwendung
EP1419150B1 (de) Phenylsulfonyl-1,3-dihydro-2h-indol-2-on derivate, deren herstellung und deren therapeutische verwendung
US7425566B2 (en) 1,3-dihydro-2H-indol-2-one derivatives, process for preparing them and pharmaceutical compositions containing them
EP1259505B1 (de) 1,3-dihydro-2h-indol-2-on derivate und deren verwendung als liganden der arginin-vasopressin rezeptoren v1b oder v1b und v1a
EP1254134B1 (de) 1,3-dihydro-2h-indol-2-on derivate und deren verwendung als liganden der arginin-vasopressin rezeptoren v1b oder v1b und v1a
EP2294068B1 (de) 1,3-dihydro-2h-pyrrolo[3.2-b]pyridin-2-onderivate, deren herstellung und deren therapeutische verwendungen
FR2722190A1 (fr) Derives de 1-benzyl-1,3-dihydro-2h-benzimidazol-2-one, leur preparation, les compositions pharmaceutique en contenant
EP1525198B1 (de) Acyloxypyrrolidinderivate und deren verwendung als liganden der v1b oder v1b und v1a rezeptoren von avp

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100920

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA RS

RIN1 Information on inventor provided before grant (corrected)

Inventor name: POUZET, BRIGITTE

Inventor name: VALETTE, GERARD

Inventor name: GOULLIEUX, LAURENT

Inventor name: SERRADEIL-LE GAL, CLAUDINE

Inventor name: FOULON, LOIC

RAX Requested extension states of the european patent have changed

Extension state: AL

Payment date: 20100920

Extension state: BA

Payment date: 20100920

Extension state: RS

Payment date: 20100920

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOFI

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA RS

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 540023

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120115

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602009004545

Country of ref document: DE

Effective date: 20120301

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: SANOFI

Free format text: SANOFI#174, AVENUE DE FRANCE#75013 PARIS (FR) -TRANSFER TO- SANOFI#54, RUE DE LA BOETIE#75008 PARIS (FR)

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: SANOFI

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: SANOFI

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20120104

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20120104

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120404

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120504

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120404

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

REG Reference to a national code

Ref country code: IE

Ref legal event code: FD4D

BERE Be: lapsed

Owner name: SANOFI

Effective date: 20120228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120405

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120504

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 540023

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120104

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120229

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

26N No opposition filed

Effective date: 20121005

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602009004545

Country of ref document: DE

Effective date: 20121005

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120415

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120104

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090218

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20190213

Year of fee payment: 11

Ref country code: DE

Payment date: 20190205

Year of fee payment: 11

Ref country code: FR

Payment date: 20190111

Year of fee payment: 11

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602009004545

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20200218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200229

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200901

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200218